Bioinformatics analysis of abnormal DNA methylation in muscle samples from monozygotic twins discordant for type 2 diabetes

Liu,Fei; Sun,Qianqian; Wang,Lingxiao; Nie,Shuangshuang; Li,Jun

doi:10.3892/mmr.2015.3452

Bioinformatics analysis of abnormal DNA methylation in muscle samples from monozygotic twins discordant for type 2 diabetes

Authors:
- Fei Liu
- Qianqian Sun
- Lingxiao Wang
- Shuangshuang Nie
- Jun Li
View Affiliations

Affiliations: Department of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China, Department of Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China, Geriatric Department, The Fifth People's Hospital of Chengdu City, Chengdu, Sichuan 610041, P.R. China, Department of Geriatrics, West China Medical College of Sichuan University, Chengdu, Sichuan 610041, P.R. China
Published online on: March 6, 2015 https://doi.org/10.3892/mmr.2015.3452
Pages: 351-356

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to examine the changes in DNA methylation of gene promoters associated with type 2 diabetes (T2D). The DNA methylation profile dataset GSE38291 was downloaded from the Gene Expression Omnibus database. A paired t‑test was used to analyze differences in the DNA methylation of gene promoters between T2D and normal muscle samples. Gene Ontology (GO) enrichment analysis was performed using online tool, The Database for Annotation, Visualization and Integrated Discovery. Whole‑Genome rVISTA was used to analyze the enriched transcription factor (TF) binding sites upstream of the transcription start site in the differentially methylated genes. A total of 38 genes, including Sirtuin 1, N‑acetyltransferase 6, phospholipase A2 group XIIB and nuclear factor of activated T cells calcineurin‑dependent 1, were identified to be differentially methylated between these two groups. One GO term, DNA geometric change (GO:0032392), was significantly enriched (P<0.05) by the hyper‑methylated genes. In addition, the binding sites of one gene, zinc finger E‑box binding homeobox 1, and three TFs, methyl CpG binding protein 2, TFEB and TFAP4, were significantly enriched in the hyper‑ and hypo‑methylated genes, respectively. The resulting T2D‑associated genes and potential TFs provided a novel insight into the molecular mechanisms underlying the pathology of T2D. These genes may become promising target genes for the development of treatments for T2D.

View Figures

View References

1	Parving H-H, Brenner BM, McMurray JJ, et al ALTITUDE Investigators: Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 367:2204–2213. 2012. View Article : Google Scholar : PubMed/NCBI
2	Kitada M and Koya D: SIRT1 in type 2 diabetes: Mechanisms and therapeutic potential. Diabetes Metab J. 37:315–325. 2013. View Article : Google Scholar : PubMed/NCBI
3	Kahn SE: The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia. 46:3–19. 2003.PubMed/NCBI
4	Spranger J, Kroke A, Möhlig M, et al: Adiponectin and protection against type 2 diabetes mellitus. Lancet. 361:226–228. 2003. View Article : Google Scholar : PubMed/NCBI
5	Hofsø D, Jenssen T, Hager H, Røislien J and Hjelmesaeth J: Fasting plasma glucose in the screening for type 2 diabetes in morbidly obese subjects. Obes Surg. 20:302–307. 2010. View Article : Google Scholar
6	Zhang P, Zhang X, Brown J, et al: Global healthcare expenditure on diabetes for 2010 and 2030. Diabetes Res Clin Pract. 87:293–301. 2010. View Article : Google Scholar : PubMed/NCBI
7	Liebl A, Mata M and Eschwège E; ODE-2 Advisory Board: Evaluation of risk factors for development of complications in Type II diabetes in Europe. Diabetologia. 45:S23–S28. 2002. View Article : Google Scholar : PubMed/NCBI
8	Sjöström L, Lindroos A-K, Peltonen M, et al Swedish Obese Subjects Study Scientific Group: Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 351:2683–2693. 2004. View Article : Google Scholar : PubMed/NCBI
9	Barres R and Zierath JR: DNA methylation in metabolic disorders. Am J Clin Nutr. 93:897S–900S. 2011. View Article : Google Scholar : PubMed/NCBI
10	Takizawa T, Nakashima K, Namihira M, et al: DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain. Dev Cell. 1:749–758. 2001. View Article : Google Scholar : PubMed/NCBI
11	Robertson KD: DNA methylation and human disease. Nat Rev Genet. 6:597–610. 2005. View Article : Google Scholar : PubMed/NCBI
12	Rönn T, Poulsen P, Hansson O, et al: Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle. Diabetologia. 51:1159–1168. 2008. View Article : Google Scholar : PubMed/NCBI
13	Ling C, Poulsen P, Carlsson E, et al: Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1β gene expression in twins. J Clin Invest. 114:1518–1526. 2004. View Article : Google Scholar : PubMed/NCBI
14	Ling C, Poulsen P, Simonsson S, et al: Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle. J Clin Invest. 117:3427–3435. 2007. View Article : Google Scholar : PubMed/NCBI
15	Jensen CB, Storgaard H, Madsbad S, Richter EA and Vaag AA: Altered skeletal muscle fiber composition and size precede whole-body insulin resistance in young men with low birth weight. J Clin Endocrinol Metab. 92:1530–1534. 2007. View Article : Google Scholar : PubMed/NCBI
16	Barrett T, Wilhite SE, Ledoux P, et al: NCBI GEO: archive for functional genomics data sets - update. Nucleic Acids Res. 41:D991–D995. 2013. View Article : Google Scholar
17	Du P, Zhang X, Huang CC, et al: Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis. BMC Bioinformatics. 11:5872010. View Article : Google Scholar : PubMed/NCBI
18	Da Wei Huang BTS, Sherman BT and Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 4:44–57. 2009. View Article : Google Scholar : PubMed/NCBI
19	Dubchak I, Munoz M, Poliakov A, et al: Whole-Genome rVISTA: a tool to determine enrichment of transcription factor binding sites in gene promoters from transcriptomic data. Bioinformatics. 29:2059–2061. 2013. View Article : Google Scholar : PubMed/NCBI
20	Wingender E, Dietze P, Karas H and Knüppel R: TRANSFAC: A database on transcription factors and their DNA binding sites. Nucleic Acids Res. 24:238–241. 1996. View Article : Google Scholar : PubMed/NCBI
21	Kume S, Uzu T, Kashiwagi A and Koya D: SIRT1, a calorie restriction mimetic, in a new therapeutic approach for type 2 diabetes mellitus and diabetic vascular complications. Endocr Metab Immune Disord Drug Targets. 10:16–24. 2010. View Article : Google Scholar : PubMed/NCBI
22	Sharma S, Misra CS, Arumugam S, et al: Antidiabetic activity of resveratrol, a known SIRT1 activator in a genetic model for type 2 diabetes. Phytother Res. 25:67–73. 2011. View Article : Google Scholar
23	Bordone L, Motta MC, Picard F, et al: Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic β cells. PLoS Biol. 4:e312006. View Article : Google Scholar
24	Bhakta S, Besra GS, Upton AM, et al: Arylamine N-acetyltransferase is required for synthesis of mycolic acids and complex lipids in Mycobacterium bovis BCG and represents a novel drug target. J Exp Med. 199:1191–1199. 2004. View Article : Google Scholar : PubMed/NCBI
25	Aljakna A, Choi S, Savage H, et al: Pla2g12b and Hpn are genes identified by mouse ENU mutagenesis that affect HDL cholesterol. PLoS One. 7:e431392012. View Article : Google Scholar : PubMed/NCBI
26	Blum M, Grant DM, Mcbride W, Heim M and Meyer UA: Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression. DNA Cell Biol. 9:193–203. 1990. View Article : Google Scholar : PubMed/NCBI
27	Heit JJ, Apelqvist AA, Gu X, et al: Calcineurin/NFAT signalling regulates pancreatic β-cell growth and function. Nature. 443:345–349. 2006. View Article : Google Scholar : PubMed/NCBI
28	Papadopoulou V, Postigo A, Sánchez-Tilló E, Porter AC and Wagner SD: ZEB1 and CtBP form a repressive complex at a distal promoter element of the BCL6 locus. Biochem J. 427:541–550. 2010. View Article : Google Scholar : PubMed/NCBI
29	Karnik SK, Chen H, McLean GW, et al: Menin controls growth of pancreatic β-cells in pregnant mice and promotes gestational diabetes mellitus. Science. 318:806–809. 2007. View Article : Google Scholar : PubMed/NCBI
30	Nan X, Ng HH, Johnson CA, et al: Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 393:386–389. 1998. View Article : Google Scholar : PubMed/NCBI
31	Li E, Beard C and Jaenisch R: Role for DNA methylation in genomic imprinting. Nature. 366:362–365. 1993. View Article : Google Scholar : PubMed/NCBI